Brain States and the Mystery of Cognition: Using magnetic resonance imaging (MRI) to map the brain

Patterns of neural activity distributed across the brain are termed “brain states”. Brain states offer a conceptual framework upon which to integrate disparate information and may be measured in many ways that differ by resolution and modality. Cognition and emotion are outputs from brain states whose precise nature is yet unknown. What is needed is an integrated framework for these different measurements. First, I will discuss our motivation for these studies, then provide some of our prior work, and finally present our current work. We combine live brain-wide imaging with molecular-genetic approaches to map and measure activity and connections across the brain under defined experiential conditions. Distributed activity between neurons located at distant sites within the brain is mediated via long projections, “axons”. Experiments in the squid giant axon revealed both electrical and chemical basis for inter-neuronal communications. Within axons, anterograde transport, an endogenous energy-driven process, carries macromolecular assemblies to the synapse from the neuronal cell body. We used manganese-enhanced magnetic resonance imaging to map neuronal projections and patterns of distributed neural activity brain-wide in 3D at 100 µm isotropic resolution. Mn(II), a paramagnetic ion, is a non-toxic contrast agent for MR, competing with endogenous calcium for entry into active neurons and transport within axons. Using localized injections of Mn(II), we mapped medial prefrontal cortical projections in mice with different genotypes. Our automated pipeline for image stack alignments together with our digital MR InVivo Atlas allows us to map Mn(II)-enhanced intensity values voxel-wise and determine the significance of signal intensity changes between conditions. We reported that genetic disruption of any one of the monoaminergic systems (serotonin, dopamine and norepinephrine) significantly perturbed mPFC projection anatomy. We then used systemic Mn(II) to map neural activity, as Mn(II) accumulates in active neurons. We found that a single experience of acute threat altered brain states both immediately and long term in the adult, with relative volumes of activity between regions imbalanced. Fragmented care in the post-natal period altered the home cage brain state as compared to normally reared mice significantly, and this altered state was further perturbed by acute threat. We used Structural Equation Modeling to test various hypotheses about participation of specific subregions into networks under different experimental conditions. Our results suggest a model for cognition in which different brain regions are active under differing conditions, and further demonstrate that experiences leave a “signature” of activity on the brain which influences how each brain state may respond to subsequent exposures. These findings have implications for both cognitive impairment in neurodegenerative diseases, emotional responses to experiences and mental dysregulation in mental illness. Our work is supported by NIH and the Harvey Family Endowment.